Comprehensive characterization of androgen receptor expression in breast cancer.
Authors: Priya Jayachandran, Sachin Deshmukh, Sharon Wu, Kathryn Therese Enriquez, Irene Kang, Joanne Xiu, Alex Patrick Farrell, Francesca Battaglin, Pooja Mittal, Janice M. Lu, Shivani Soni, Wu Zhang, Joshua Millstein, Cynthia X. Ma, Stephanie L. Graff, Milan Radovich, Heinz-Josef Lenz, Darcy V. Spicer, George W. Sledge, Evanthia T. Roussos Torres
Journal: Journal of Clinical Oncology (2023)

1035 Background: The androgen receptor ( AR) is a hormone-regulated transcription factor that plays an important role in breast cancer (BC) pathogenesis. While estrogen receptor inhibitors are well-studied in BC, the role of AR on prognosis and therapy is less well-known. Here we aim to characterize the clinicopathologic and molecular features of AR expression in BC. Methods: 27,169 BC samples were tested by NGS (592, NextSeq; WES, NovaSeq), WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Microsatellite-instability (MSI) was tested by IHC and NGS. Tumor mutational burden (TMB) totaled somatic mutations per tumor (high≥10 mt/MB). Tumors with AR-high(H) and AR-low(L) expression were classified by top and bottom quartile, respectively. Real world overall survival (OS) and treatment-associated survival was obtained from insurance claims and calculated from tissue collection or treatment start to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q&lt;0.05). Results: Median AR expression was higher in lobular compared to ductal carcinoma (2.2-fold) and in HR + /HER2 - compared to TNBC (13.9-fold). Compared to AR-L, AR-H BC had higher frequency of PIK3CA (50.6% vs 12.7%), CDH1 (20% vs 2.2%), ESR1 (12.8% vs 1.4%), MAP3K1 (9.4% vs 1.4%), GATA3 (11.2% vs 2.7%), AKT1 (5.7% vs 1.4%), NF1 (8.6% vs 3.6%), ARID1A (6.9 vs 3.6), SPEN (2.8% vs 1.5%), and PTEN (7.9% vs 6.2%) mutations and TMB high (9.5% vs 7.7%), but lower frequency of dMMR/MSI-H (0.6% vs 1.7%) and PD-L1 (18.7% vs 45.3%) positivity (all p&lt;0.05). AR-H tumors also showed enrichment of the IL2-STAT5 pathway (NES: 1.33, FDR: 0.24). Further, AR-H BC had higher expression of immune checkpoint genes ( CD274, PDCD1LG2, LAG3, HAVCR2, FOXP3, FC: 1.1-1.4, all p&lt;0.05) and T cell inflamed scores (32.5% vs 26.2%, p&lt;0.05). AR-H BC had increased immune cell infiltration of B cells (6% vs 4%), M2 Mφ (5% vs 2%), and NK cells (3% vs 2%), but decreased infiltration of M1 Mφ (2% vs 3%) (all p&lt;0.05). AR-H BC had upregulation of M2 Mφ related genes ( ARG1, IL10, CCL17, CXCR1, FC: 1.2-1.8, all p&lt;0.05) and downregulation of M1 Mφ related genes ( CCL2, CCL5, CXCL9, CXCL10, FC: 1-1.5, all p&lt;0.05). AR-H BC was associated with improved OS compared to AR-L BC (mOS: 1843 vs 1096 days; HR 0.6, 95% CI 0.5-0.7, p&lt;0.00001), and with doxorubicin (2294 vs 2054 days; HR 0.7, 95% CI 0.5-0.9, p&lt;0.001) , paclitaxel (2239 vs 1967 days; HR 0.7, 95% CI 0.5-0.9, p&lt;0.001) and trastuzumab (inf vs 2351 days; HR 0.6, 95% CI 0.4-0.9, p&lt;0.01) treatment. Conclusions: Our data suggest a strong association between AR expression and increased mutations in several cancer related genes, immune checkpoint markers, the IL2-STAT5 pathway, differential immune cell infiltration, and improved overall survival.